1,4-dihydropyridines

ABSTRACT

Dihydropyridines of formula I ##STR1## wherein R is hydrogen or lower alkyl; R 1  is a CN, NO 2 , COCH 3 , COPh group, a carboalkoxy or carboamide group; R 2  is an aromatic or heteroaromatic, mono- or bicyclic eventually substituted phenyl group; R 3  is a carboalkoxy group; while A is a halogen atom or an ammonium or phosphonium residue. The compounds I are useful as antihypertensive, antitumoral, antimetastatic, antithrombotic, and/or antiischemic agent.

The present invention relates to 2-(phosphonium orammonium-methyl)-1,4-dihydropyridine salts and to their 2-halomethylintermediates, to a method for their preparation and to pharmaceuticalcompositions containing them.

The compounds of the invention have the following general formula I:##STR2## wherein R is hydrogen or C₁ -C₅ lower alkyl;

R₁ represents acetyl, benzoyl, cyano, nitro, an esterified carboxy groupCO₂ R₄ or an amide --CONR₅ R₆ ;

R₂ is a member selected from the group consisting of:

(a) a phenyl group unsubstituted or substituted by one or more C₁ -C₆alkoxy, halo-C₁ -C₆ alkyl, halo-C₁ -C₄ alkoxy, halogen, nitro, cyano, C₁-C₆ alkoxycarbonyl, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulphinyl groups;

(b) pentafluorophenyl;

(c) α or β-naphthyl;

(d) a five or six-membered-heterocyclic ring;

(e) α-benzo[2,3-b]-1,4-dioxane-α-yl, or

(f) α-benzo[3,4-c]-furoxanyl;

R₃ is an esterified carboxy group CO₂ R₄ ;

R₄ is a member selected from the group consisting of a C₁ -C₆ alkylchain unsubstituted or substituted by hydroxy, amino, monoalkylamino,dialkylamino, C₁ -C₆ alkoxy groups; C₃ -C₆ alkenyl; an optionallysubstituted aryl or C₁ -C₄ aralkyl group;

each of R₅ and R₆, which are the same or different, may be hydrogen, C₁-C₆ alkyl, benzyl or aryl;

A represents a chlorine, bromine or iodine atom or a phosphonium(.sup.(+) PR₇ R₈ R₉ X⁻) or ammonium (.sup.(+) NR₁₀ ^(R) ₁₁ R₁₂ X⁻) groupwherein each of R₇ R₈ and R₉, which are the same or different, may be aC₁ -C₆ lower alkyl, a substituted or unsubstituted aryl or C₁ -C₄aralkyl; R₁₀, R₁₁ and R₁₂ which are the same or different may be C₁ -C₆lower alkyl or one of R₁₀, R₁₁, R₁₂ is as defined above and the othertwo form a ring when taken together with the nitrogen atom to which theyare linked; or one of R₁₀, R₁₁, R₁₂ is a bond and the other two, whentaken together which the nitrogen atom to which they are linked, form aheterocyclic ring optionally substitued with a halogen, C₁ -C₆ alkyl, C₁-C₆ alkoxy, a free or esterified CO₂ R₄ group as defined, --C.tbd.N,--CONH₂, a substituted or unsubstituted aryl;

X⁻ is a pharmaceutically acceptable anion,

The optical antipodes, i.e. the enantiomers, and racemic mixture of theoptical antipodes of the compounds of formula (I) are also included inthe scope of the present invention.

A halo-C₁ -C₆ alkyl group is preferably trihalo-C₁ -C₆ alkyl, inparticular trifluoromethyl.

A halo-C₁ -C₄ alkoxy group is preferably difluoromethoxy.

A C₁ -C₆ alkyl group is preferably methyl, ethyl, isopropyl ortert-butyl.

An aryl group is preferably phenyl.

A C₃ -C₆ alkenyl is preferably allyl.

A monoalkylamino radical is preferably a methyl, ethyl, isopropyl orbenzylamino group.

A dialkylamino group is preferably a dimethylamino, diethyl, benzyl- ormethylamino group.

A dialkylamino group is more preferably a residue wherein the dialkylsubstituent is part of a cyclic residue such as pyrrolidin-1-yl,piperidin-1-yl, pyperazin-yl, 4-substituted-pyrazin-1-yl, imidazol-1-yl,2-alkoxycarbonyl-pyrrolidin-1-yl.

A C₁ -C₄ aralkyl group is preferably benzyl.

X.sup.(-) is preferably Cl⁻, Br⁻, I⁻, CH₃ SO₃.sup.(-), ClO₄.sup.(-),BF₄.sup.(-), CH₃ CO₂.sup.(-) and (p)CH₃ --C₆ H₅ --SO₃.sup.(-). R ispreferably hydrogen, CONR₅ R₆ is preferably --CONH₂ ; R₇, R₈, R₉ arepreferably the same and more preferably they are n-butyl or phenylgroups.

The preferred quaternary ammonium salts of formula NR₁₀ R₁₁ R₁₂ are1-methylpiperidinium, triethylammonium and diaza[2,2,2]bicyclooctanium.

Preferred heteroaromatic quaternary ammonium salts are pyridinium,pyrimidinium, pyrazinium, 1-imidazolinium, oxazolium, thiazolium andpyrazolium salts. Specific examples of preferred compounds of theinvention are hereinbelow reported:

2-chloromethyl-3,5-dicarboethoxy4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3,5-dicarboethoxy-4-(m-chlorophenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3,5-dicarboethoxy-4-(o-methylthiophenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3-carbomethoxy-5-carboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3-carboethoxy-5-acetyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3-carboethoxy-5-cyano-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine;

2-iodomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine;

2-chloromethyl-3-carboethoxy-5-nitro-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine;

[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triethylphosphoniumchloride;

[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]tributylphosphoniumchloride;

[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;

[(6-methyl-3,5-dicarboethoxy-4-(o-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;

[(6-methyl-3,5-dicarboethoxy-4-(o-chlorophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;

[(6-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;

[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumiodide;

[(6-methyl-3-cyano-5-carboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;

1-[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]pyridiniumchloride;

1-[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]-3-carbamoylpyridinium chloride;

1-[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]1,4-[2,2,2]-diazabicyclooctaniumchloride.

The compounds of the invention are prepared by a process comprising:

cyclization of a compound of formula II ##STR3## wherein R, R₁, R₂, R₄are as above defined, X' is chlorine or bromine, the symbols and , whichare the same or different, represent a single or a double bond and D andC are respectively NH₂ and OH when the symbols , are a double bond orthey are ═NH and ═O when the symbols , are a single bond, to give acompound of formula Ia ##STR4## wherein R, R₁, R₂, R₄ and X' are asdefined above.

The compounds Ia, if desired, may be optionally converted into acompound of formula Ia wherein X' is iodine or by the reaction with aphosphine (R₇ R₈ R₉ P) or an amine (R₁₀ R₁₁ R₁₂ N) wherein R₇, R₈, R₉,R₁₀, R₁₁, R₁₂ are as above defined to give a compound of formula Iwherein A is a quaternary salt which may be optionally transformed, ifdesired, into another quaternary salt having a different,pharmaceutically acceptable anion.

The cyclization of a compound II may be carried out in an inert solventeither in the presence or in absence of an acid catalyst such as ahydrohalogen acid, sulfuric acid, an alkyl or an aryl sulfonic acid,formic, acetic, or trifluoroacetic acids.

Suitable solvents are C₁ -C₄ lower alcohols such as methanol, ethanol,isopropanol, n-butanol and isobutanol, aromatic hydrocarbons such asbenzene, toluene; linear and cyclic ether such as dimethoxyethane,tetrahydrofuran or an ester i.e. ethylacetate, as well as mixturesthereof.

The cyclization reaction is preferably carried out from -20° C. to theroom temperature, preferably at about 0° C.

The reaction times range from few minutes to several hours, but usuallydo not exceed two hours and often a few minutes are sufficient tocomplete the reaction when the acid catalyst is added. The preferredamounts of the acid catalyst range from 0.01 to 0.1 molar equivalents.

The formation of a quaternary salt (I) may be carried out by reaction ofa compound of formula (Ia) with either a stoichiometric amount or asmall excess of a trisubstituted phosphine or amine of formula (III), inan inert solvent.

Suitable solvents are C₁ -C₄ lower alcohols, i.e. methanol, ethanol;aromatic hydrocarbons such as benzene or toluene and ethers, ketones,nitriles or esters such as dimethoxyethane, tetrahydrofuran, acetone,butanone, ethylacetate, acetonitrile, as well as mixture thereof.

The reaction is preferably carried out at temperature ranging from about0° C. to the reflux temperature of the reaction mixture, preferably fromthe room temperature to 80° C.

The compounds of formula II are obtained by reacting a compound offormula III ##STR5## wherein R₂, R₃ and X' are as defined above, witheither a stoichiometric amount of a small excess of a compound offormula IV ##STR6## in an inert solvent, as above defined, such as a C₁-C₄ lower alcohol, an aromatic hydrocarbon, a linear or cyclic ether, anester or mixtures thereof.

The reaction between compounds III and IV must be carried out underkinetic control, at a temperature ranging from little more the roomtemperature to the reflux temperature.

When the reaction is over, the mixture is rapidly cooled to 15÷0° C. andthe product may be recovered in pure form or directly used in theprocess of the invention.

The reaction times range from few minutes to few hours, but usually donot exceed two hours and often a few minutes are sufficient to completethe reaction. Kinetic control means that the reaction time is strictlyrelated to the heating temperature of the reaction mixture.

The compounds III are obtained by reaction of an aldehyde of formula V:

    R.sub.2 --CHO                                              (V)

wherein R₂ is as defined above, with a 4-halo-3-oxo-butanoate of formulaVI: ##STR7## wherein R₄ and X' are as above defined using proceduresknown in the art, for example Knoevenagel reaction, i.e. refluxing thealdehyde and the β-ketoester in an inert solvent, e.g. benzene ortoluene, in the presence of piperidine acetate, removing the waterformed during the reaction.

Alternatively, a compound of formula III may be also prepared startingfrom another compound of formula III wherein X' is hydrogen, accordingto well known halogenation procedures of the angular methyl group (--CH₂X'═CH₃).

The compounds of formula IV are known compounds, commercially available,or easily preparable with known methods, for example by hydrogenolyticcleavage of known isoxazole precursors such as the compounds VII a-c##STR8## wherein R, R₄, R₅, R₆ are as above defined and R'₁ is methyl orphenyl. The compounds of the invention, and particularly those wherein Ais an halogen atom or a triphenylphosphonium group, may also be used asstarting material for subsequent reactions such as substitutionreactions or Wittig reactions with carbonyl compounds. The compounds ofthe invention may be therefore useful as intermediates for thepreparation of the compounds disclosed in the Italian Pat. Appln. No.21944 A/85 and 21876 A/85 in the applicant's name.

Some 2-chloromethyl-1,4-dihydropyridines of formula I wherein R ishydrogen and R₁ is a carboxyester group are described in the patentliterature, see for example DE-A-2629842 (27.01.1977) and E.P. Appln.No. 0083315 (6.07.1983), both disclosing as starting materials 2-(or6-)hydroxymethyl-1,4-dihydropyridines, prepared by multi-step processes;the exchange of the hydroxy group with a chlorosubstituent is carriedout using conventional procedures well-known in preparative organicchemistry, for example by means of triphenylphosphine and CCl₄ orthionyl chloride. The crude chloromethyl derivatives are used asintermediates for the preparation of 2-cyanomethyl and of2-(N,N-dialkylaminomethyl)-dihydropyridines. 2-Chloromethyl derivativesare also known from E.P. Appln. No. 0083315 as possible intermediates inthe preparation of furo[3,4-b]dihydropyridines of formula VIII ##STR9##from an aldehyde such as R₂ CHO, an alkyl 4-chloro-3-oxo-butanoate andan alkylaminocrotonate.

In principle, the supposed formation of 2(or6)-halomethyl-1,4-dihydropyridines, as intermediates in the synthesis ofthe above-mentioned lactones, is based on the easy ring closure ofalkyl-4-halo-3-oxo-butanoates and ofZ-alkyl-4-halo-2,3-disubstituted-2-butanoates to furanones by alkylhalide elimination. This well-known ring closure reaction is extremelyfavoured by heating and sometimes may take place spontaneously afterlong periods at room temperature, too.

In fact, when the reaction of a compound III with a compound IV is notcarried out under kinetic control in order to isolate the adduct offormula II by rapid cooling of the reaction mixture, the correspondinglactones of formula VIII are formed, as predominant reaction products.

The synthesis of lactones of formula VIII is also described in asubsequent E.P. Appln. No. 0111453 (20.06.1984) by reaction of analdehyde with a β-aminocrotonate and 4-chloro-3-oxo-butanoate in ethanolfor 30 hours. In said references, the 2 or (6)-halomethyldihydropyridines are cited only as intermediates and no therapeuticactivity is reported.

The compounds of the invention show an antagonistic properties "invitro" and antihypertensive activity "in vivo" after oraladministration.

For example the compounds of the invention are able to inhibit "invitro" the contractions induced by CaCl₂, in K⁺ -depolarized aortastrips, when tested according to the Godfraind's procedure (T. Godfraindet al., Arch. Intern. Pharmacodyn. 172, 235, 1968), in comparison withnifedipine, a known Ca-antagonist drug, as reference compound.

The compounds of the invention exhibit ID₅₀ values ranging from 1.5.10⁻⁸and 3.10⁻⁹, in comparison with an ID₅₀ of 2.7.10⁻⁸ for the referencesubstance.

The antihypertensive activity of the compounds of the invention wasinvestigated in spontaneously hypertensive rats (SH rats) measuring thedecrease of the mean blood pressure after oral administration.

Many compounds of the invention, when administered at a dose level lowerthan 1/10 of their LD₅₀, show a 15% decrease of the mean blood pressure(mean BP) with respect to the basal value, at least. This 15% decreaseof the mean BP is generally considered to be a predictive proof for asignificant cardiovascular activity.

Receptorial binding studies on cerebral rat membranes show that thequaternary ammonium salts are endowed with good affinities. Saidcompounds, when administered orally to SH rats, don't induce aremarkable antihypertensive effect, but a decrease of the heart rate isobserved.

Some compounds of the invention were tested in order to assess theirpotential as inhibitors of the growth of tumoral cells in vitro and inparticular the phosphonium salts show inhibitory activity at a finaldilution of 1-10 μg/ml in the growth medium.

Representative compounds of the invention are2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridines,for which a decrease in the mean BP of 45 mmHg is observed after oraladministration to conscious SH rates at a dosage of 10 mg/kg (DL₅₀ >1 gin normal rats by oral route), and[3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine-2-yl]methyl-triphenylphosphoniumchloride.

For the latter compound, a decrease of 56 mmHg in the mean BP isobserved after oral administration of 3 mg/kg to SH rats (LD₅₀ >1000 byoral route).

The compounds of the invention are also able to protect cellularmembranes from oxidative injuries. A decreased production ofmalondialdehyde is observed after incubation of rat erithrocytemembranes with the compounds of the invention (test of M. Aishita etal., Arch. Intern. Pharmacodyn., 261, 316, 1983).

Sudden death of mice, induced by bolus administration of a mixture ofcollagene and ADP mixture, is prevented by previous oral administrationof the compounds of the invention.

The compounds of the invention ae consequently able to interact withintracellular availability of calcium ions and they are therefore usefulfor the regulation of metabolic processes involved in the contraction ofsmooth vascular muscles.

The compounds of the general formula I are therefore useful asvasodilators, antihypertensive agents as well as antithrombotic andantimetastatic drugs. To obtain the desired therapeutic effect, thecompounds of the invention of the formula I may be administered to thepatient in different ways, alone or in pharmaceutical preparation byoral or parenteral route, i.e. intravenously or intramuscularly. Apharmaceutical composition suitable for this purpose can be preparedaccording to the known techniques, as described for instance in"Remington's Pharmaceutical Sciences Handbook", Hack Publishing Company,U.S.A.

The administered amounts vary according to the gravity of the treateddisease and to the administration route. If administered orally, thequantity of the active principle administered varies from 0.01 mg/kg to10 mg/kg of the patient's body weight pro die. If administeredparenterally, the amount of active principle varies from 0.001 mg/kg to5 mg/kg of patient's body weight pro die and it is preferably comprisedbetween 0.01 mg/kg and 2 mg/kg of patient's body weight pro die.

A single dose for oral administration may contain for example from 0.05to 100 mg of active principle. A single dose for parenteraladministration may contain, for example, from 0.05 to 70 mg of activeprinciple.

The compounds of the invention, because of their long lasting effect,may be administered once or twice a day; however repeated dailyadministrations could be--at least in some cases--desirable and may varyaccording to the patient's conditions or the administration route. Theword "patient" means not only human beings, but generally warm-bloodedanimals.

For the oral administration, the compound may be formulated in solid orliquid preparations such as capsules, pills, tablets, powders,solutions, suspensions or emulsions. The unit dosage form may be thehard or soft gelatine capsule containing for instance lubricants andinert excipients such as lactose, saccharose or starch. Alternatively,the compounds of the invention may be administered as tablets, oncarriers such as lactose, saccharose or starch in combination withbinders such as starch itself or gelatin, disintegrating agents such aspotato starch, or alginic acid, and lubricants such as stearic acid andmagnesium stearate.

For parenteral administration the compounds of the invention may beadministered in injectable forms, dissolved or suspended inpharmaceutically acceptable diluents, with a pharmaceutical carrier suchas a sterile liquid such as water or an oil, with or without theaddition of other pharmaceutically acceptable excipients. Oils which maybe used in said preparations are of mineral, vegetal, animal orsynthetic kind. Generally, as a carrier for injectable solutions thefollowing substances may be used: water, salts, aqueous solutions,dextrose or other sugars aqueous solutions, ethanol, glycols such aspropylenglycol and polyethylenglycols.

For the rectal administration, the compounds may be formulated in formsof suppositories, mixed with conventional vehicles such as, for example,cocoa butter, wax, polyvinylpyrrolidone or polyoxyethyleneglycols, orderivatives thereof.

The administration route generally preferred is the oral route, whilethe preferred pharmaceutical formulations are capsules.

The invention is illustrated by the following non limitative examples,wherein the abbreviation Et₂ O, EtOH, AcOEt, CH₃ CN, MeOH, refer todithylether, ethanol, ethylacetate, acetonitrile, methanol,respectively.

EXAMPLE 1

A mixture of ethyl 4-chloroacetate (108 g), m-nitrobenzaldehyde (100 g),acetic acid (7.2 ml) and piperidine (2.6 ml) in benzene (800 ml) isheated to the reflux temperature, in a Dean-Stark apparatus providedwith a water separator, for two hours, then it is cooled to roomtemperature, washed with water (5×50 ml), dried on Na₂ SO₄ andevaporated to dryness. The residue is dissolved in Et₂ O (200 ml) togive 85 g of ethyl 2-(m-nitrophenylmethylen)-4-chloro-3-oxo-butanoate,m.p. 108°-111° C.

EXAMPLE 2

Using in the procedure described in Example 1 a substituted-benzaldehydeand an alkyl 2-(substituted-phenyl)-3-oxo-butanoate the compounds listedhereinbelow are prepared:

    ______________________________________                                         ##STR10##                                                                    R.sub.2          R.sub.4                                                                              m.p. (°C.)                                     ______________________________________                                        C.sub.6 H.sub.5  Et     oil                                                   o-ClC.sub.6 H.sub.4                                                                            Et     oil                                                   m-ClC.sub.6 H.sub.4                                                                            Et     oil                                                   p-FC.sub.6 H.sub.4                                                                             Et     oil                                                   o-NO.sub.2 C.sub.6 H.sub.4                                                                     Et     112-116                                               p-NO.sub.2 C.sub.6 H.sub.4                                                                     Et     89-91                                                 m-NO.sub.2 C.sub.6 H.sub.4                                                                     Me     148-150                                               m-NO.sub.2 C.sub.6 H.sub.4                                                                     t-But  88-90                                                 o-CF.sub.3 C.sub.6 H.sub.4                                                                     Et     oil                                                   m-CF.sub.3 C.sub.6 H.sub.4                                                                     Et     oil                                                   m-OCH.sub.3 C.sub.6 H.sub.4                                                                    Et     oil                                                   o-SCH.sub.3 C.sub.6 H.sub.4                                                                    Et     oil                                                   β-pyridyl   Et     oil                                                   α-thienyl  Et     oil                                                   ______________________________________                                    

EXAMPLE 3

A solution of ethyl 2-(m-chlorophenylmethylen)-4-chloro-3-oxobutanoate(5 g) and ethyl-3-aminocrotonate (2.3 g) in EtOH (50 ml) is stirred atroom temperature for four hours, then it is evaporated at reducedpressure, the residue dissolved in Et₂ O (70 ml) washed with water (3×20ml), dried on Na₂ SO₄ and purified by column-chromatography on silicagel (120 g; eluent hexane/AcOEt 60/40) to give 4.2 g of2-amino-7-chloro-3,5-dicarboethoxy-6-oxo-4-(m-chlorophenyl)-2-heptene asan oil.

NMR (CDCl₃) δ (TMS): 1.00-1.30 (6H, t); 2.20-3.80 (7H, m); 4.00-4.20(4H, q); 7.00-7.30 (4H, m); 7.60-8.00 (2H, m; exchanges with D₂ O).

EXAMPLE 4

A solution of ethyl2-(m-trifluoromethylphenyl-phenylmethyl)-4-chloro-3-oxobutanoate (8 g)and ethyl 3-aminocrotonate (3.4 g) in EtOH (80 ml) is heated to refluxtemperature for 10 minutes, then it is cooled at room temperature andafter usual work-up the residue is purified by column-chromatography onsilica-gel (300 g, eluent Et₂ O/isopropylether 50/50) to give 6 g of2-amino-7-chloro-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-6-oxo-2-hepteneas an oil.

NMR (CDCl₃) δ (THS): 1.10-1.30 (6H t); 2.30-3.80 (7H, m); 3.90-4.20 (4H,q); 7.00-8.10 (6H, m; partially exchanges with D₂ O).

EXAMPLE 5

Using in the procedure described in Examples 3-4 a suitable alkyl2-(substituted methylene)-4-chloro-3-oxo-butanoate and an alkyl3-aminocrotonate the following 2-amino-7-chloro-6-oxo-2-heptenederivatives are prepared:

3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl);

3,5-dicarboethoxy-4-(m-nitrophenyl);

3-carboethoxy-5-carboisopropoxy-4-(m-nitrophenyl);

3,5-dicarboethoxy-4-phenyl;

3,5-dicarboethoxy-4-(p-fluorophenyl);

3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethylphenyl).

EXAMPLE 6

A solution of2-amino-7-chloro-3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethylphenyl)-6-oxo-2-heptene(5 g) and aqueous concentrated HCl (0.2 ml) in EtOH (50 ml) is stirredat 0° C. for 2 hours then it is neutralized with a drop of a saturatedNaHCO₃ solution and evaporated to dryness. The residue is dissolved inAcOEt (50 ml), washed with water (3×15 ml), dried on Na₂ SO₄ andconcentrated in vacuum. The residue is dissolved in Et₂O/diisopropylether to give 3.6 g of2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethylphenyl)-6-methyl-1,4-dihydropyridine,m.p. 115°-116° C.

EXAMPLE 7

A mixture of ethyl 2-(m-nitrophenylmethylene)-4-chloro-3-oxobutanoate(80 g) and methyl 3-aminocrotonate (32.7 g) in EtOH (800 ml) is heatedto reflux temperature for 15 minutes, then, without isolating the formedintermediate,2-amino-7-chloro-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-oxo-2-heptene,the mixture is cooled at 0° C. and acidified with aqueous concentratedHCl (3 ml). After two hours the reaction mixture is neutralized with afew drops of a saturated NaHCO₃ solution and evaporated to dryness. Theresidue is dissolved in AcOEt (400 ml), washed with water (4×50 ml),dried on Na₂ SO₄ and concentrated in vacuum. The residue is dissolved inEt₂ O to give 80 g of2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine(m.p. 119°-120° C.).

EXAMPLE 8

Using in the procedure described in Example 6 a suitable2-amino-6-oxo-2-heptene or in the procedure described in Example 7 anenamine selected from alkyl 3-aminocrotonate, 3-aminocrotononitrile,2-amino-3-nitro-2-propene, 4-amino-3-penten-2-one,3-amino-1-phenyl-2-buten-1-one and a suitable alkyl 2-(substitutedmethylene)-4-chloro-3-oxo-butanoate, the following 1,4-dihydropyridinesare obtained:

    __________________________________________________________________________     ##STR11##                                                                    R.sub.1          R.sub.2  R.sub.4                                                                             M.p. (°C.)                             __________________________________________________________________________    CO.sub.2 Et      m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    129-131                                       CO.sub.2 Et      o-NO.sub.2 C.sub.6 H.sub.4                                                             Et    115-116                                       CO.sub.2 Me      m-NO.sub.2 C.sub.6 H.sub.4                                                             Me    oil                                           CO.sub.2 C.sub.3 H.sub.7 i                                                                     m-NO.sub.2 C.sub.6 H.sub.4                                                             Et     99-102                                       CO.sub.2 Me      m-NO.sub.2 C.sub.6 H.sub.4                                                             C.sub.4 H.sub.9 t                                                                   oil                                           CO.sub.2 C.sub.4 H.sub.9 t                                                                     m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    80-84                                         CO.sub.2 Me      p-NO.sub.2 C.sub.6 H.sub.4                                                             Et    135-137                                       CO.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                 m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    oil                                           CO.sub.2 Me      C.sub.6 H.sub.5                                                                        Et    82-85                                         CO.sub.2 Me      o-CF.sub.3 C.sub.6 H.sub.4                                                             Et    oil                                           CO.sub.2 Et      o-CF.sub.3 C.sub.6 H.sub.4                                                             Et    oil                                           CO.sub.2 Me      o-ClC.sub.6 H.sub.4                                                                    Et    oil                                           CO.sub.2 Et      o-ClC.sub.6 H.sub.4                                                                    Et    50-52                                         CO.sub.2 Me      m-ClC.sub.6 H.sub.4                                                                    Et    109-111                                       CO.sub.2 Et      o-SCH.sub.3 C.sub.6 H.sub.4                                                            Et    oil                                           CO.sub.2 Me      m-OCH.sub.3 C.sub.6 H.sub.4                                                            Et    136-138                                       CO.sub.2 Me      p-FC.sub.6 H.sub.4                                                                     Et    115-117                                       CN               m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    151-152                                       NO.sub.2         m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    158-160                                       COCH.sub.3       m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    oil                                           COC.sub.6 H.sub.5                                                                              m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    oil                                           CO.sub.2 Et      β-pyridyl                                                                         Et    oil                                           CO.sub.2 Et      α-thienyl                                                                        Et    oil                                           CO.sub.2 CH(CH.sub.3)φ                                                                     m-NO.sub.2 C.sub.6 H.sub.4                                                             Et    oil                                           __________________________________________________________________________

EXAMPLE 9

A mixture of2-chlorometyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine(0.5 g) and potassium iodide (1 g) in acetone (5 ml) is stirred at roomtemperature for 24 hours, then it is filtered, concentrated underreduced pressure and the residue purified by column chromatography onsilica gel (20 g, eluent: hexane/AcOEt 80/20) to give 0.22 g of2-iodomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridineas an oil.

NMR (CDCl₃) δ (THS): 1.10-1.30 (6H, t); 2.20 (3H, s);

3.90-4.20 (4H, q); 5.10 (1H, m); 5.20-5.30 (2H, dd); 6.70 (1H, m);7.10-8.10 (4H, m).

EXAMPLE 10

A mixture of2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine(6 g) and triphenylphosphine (4 g) in CH₃ CN (60 ml) is heated to refluxtemperature for six hours, then it is evaporated in vacuum and theresidue crystallized from EtOH to give 6.5 g of[6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl]methyltriphenylphosphoniumchloride, m.p. 225°-227° C.

EXAMPLE 11

Using in the procedure of Example 6 a suitable2-halomethyl-1,4-dihydropyridine and a phosphine selected in the groupof triphenylphosphine, tributylphosphine and triethylphosphine, thefollowing compounds are obtained:

    ______________________________________                                         ##STR12##                                                                    R.sub.1 R.sub.2     R.sub.4 R.sub.7                                                                              X   M.p. (°C.)                      ______________________________________                                        CO.sub.2 Et                                                                           m-NO.sub.2 C.sub.6 H.sub.4                                                                Et      n-C.sub.4 H.sub.9                                                                    Cl  90-92                                  CO.sub.2 Et                                                                           m-NO.sub.2 C.sub.6 H.sub.4                                                                Et      n-C.sub.4 H.sub.9                                                                    I                                          CO.sub.2 Me                                                                           m-NO.sub.2 C.sub.6 H.sub.4                                                                Et      C.sub.6 H.sub.5                                                                      Cl  196-199                                CO.sub.2 Me                                                                           m-NO.sub.2 C.sub.6 H.sub.4                                                                Et      n-C.sub.4 H.sub.9                                                                    Cl                                         CO.sub.2 Me                                                                           o-ClC.sub.6 H.sub.4                                                                       Et      C.sub.6 H.sub.5                                                                      I                                          CO.sub.2 Et                                                                           o-CF.sub.3 C.sub.6 H.sub.4                                                                Et      n-C.sub.4 H.sub.9                                                                    Cl                                         CN      m-NO.sub.2 C.sub.6 H.sub.4                                                                Et      C.sub.6 H.sub.5                                                                      Cl  173-176                                NO.sub.2                                                                              m-NO.sub.2 C.sub.6 H.sub.4                                                                Et      n-C.sub.4 H.sub.9                                                                    Cl                                         CO.sub.2 Et                                                                           β-pyridyl                                                                            Et      n-C.sub.4 H.sub.9                                                                    Cl                                         CO.sub.2 Et                                                                           α-thienyl                                                                           Et      n-C.sub.4 H.sub.9                                                                    Cl                                         CO.sub.2 Et                                                                           m-NO.sub.2 C.sub.6 H.sub.4                                                                Et      C.sub.2 H.sub.5                                                                      Cl                                         ______________________________________                                    

EXAMPLE 12

A solution of2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophyenyl)-6-methyl-1,4-dihydropyridine(5 g) and pyridine (15 ml) in acetone (20 ml) is heated to refluxtemperature for six hours, then it is cooled at room temperature,stirred for two hours and the formed crystaline precipitate is filteredoff. Recrystallization from MeOH/acetone (70/30) gives 4.9 g of1-[6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl]methyl-pyridiniumchloride, m.p. 182°-184° C.

EXAMPLE 13

Using in the above described procedure a suitable tertiary amine orheteroaromatic aza compound and a halomethyl-1,4-dihydropyridine, thefollowing compounds are obtained:

1-[6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl]methyl-3-carbamoylpyridiniumchloride, m.p. 210°-211° C.;

[6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl]methyltributylammoniumchloride, m.p. 118°-120° C.;

1-[6-methyl-3-carboethoxy-5-carbomethoxy-4-(o-chlorophenyl)-1,4-dihydropyridin-2-yl]methylpyridiniumchloride;

1-[6-methyl-3,5-dicarboethoxy-4-phenyl-1,4-dihydropyridin-2-yl]methyl-pyridiniumiodide;

1-[6-methyl-3,5-dicarboethoxy-4-(m-trifluoromethylphenyl)-1,4-dihydropyridin-2-yl]methyl-3-carboethoxypyridiniumchloride;

1-[6-methyl-3-carboethoxy-5-cyano-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl]methyl-pyridiniumchloride;

1-[6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl]-1,4-[2,2,2]diazabicyclooctaniumchloride trihydrate, m.p. 133°-135° C.;

1-[6-methyl-3,5-dicarboethoxy-4-(α-thienyl)-1,4-dihydropyridin-2-yl]methyl-triethylammoniumchloride;

1-[6-methyl-3,5-dicarboethoxy-4-(o-methylthiophenyl)-1,4-dihydropyridin-2-yl]methyl-3-methylimidazoliumchloride.

We claim:
 1. A compound of the formula I ##STR13## wherein R is hydrogenor C₁ -C₅ lower alkyl;R₁ represents acetyl, benzoyl, cyano, nitro, anesterified carboxy group CO₂ R₄ or an amide --CONR₅ R₆ ; R₂ is a memberselected from the group consisting of:(a) a phenyl group unsubstitutedor substituted by one or more C₁ -C₆ alkoxy, halo-C₁ -C₆ alkyl, halo-C₁-C₄ alkoxy, halogen, nitro, cyano, C₁ -C₆ alkoxycarbonyl, C₁ -C₆alkylthio, C₁ -C₆ alkylsulphinyl groups; (b) pentafluorophenyl; (c) α-or β-naphthyl; (d) 2-thienyl or β-pyridyl; (e)α-benzo[2,3-b]-1,4-dioxane-α-yl, or (f) α-benzo[3,4-c]-furoxanyl; R₃ isan esterified carboxy group CO₂ R₄ ; R₄ is a member selected from thegroup consisting of a C₁ -C₆ alkyl chain unsubstituted or substituted byhydroxy, amino, benzylamino, alkylamino selected from the groupconsisting of methylamino, ethylamino and isopropylamino, dialkylaminoselected from the group consisting of dimethylamino and diethylamino,heterocycle selected from the group consisting of pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, imidazol-1-yl, and2-alkoxycarbonyl-pyrrolidin-1-yl, and C₁ -C₆ alkoxy groups; C₃ -C₆alkenyl; phenyl or (C₁ -C₄ alkyl) phenyl; each of R₅ and R₆, which arethe same or different, may be hydrogen, C₁ -C₆ alkyl, benzyl or phenyl;A represents a phosphonium group or a quaternary ammonium grop, saidphosphonium group having the formula .sup.(+) PR₇ R₈ R₉ X⁻ wherein eachof R₇, R₈ and R₉, which are the same or different, may be a C₁ -C₆ loweralkyl, phenyl, or (C₁ -C₄ alkyl) phenyl; said quaternary ammonium groupbeing selected from the formulas IX, X and XI:

    .sup.(+) NR.sub.10 R.sub.11 R.sub.12 X.sup.-               (IX)

wherein each of R₁₀, R₁₁ and R₁₂, which are the same or different, is aC₁ -C₆ lower alkyl; ##STR14## wherein R¹⁰ is a C₁ -C₆ lower alkyl, and Eis a group which forms with the quaternary nitrogen atom a piperidiniumring; ##STR15## wherein G is a group which forms with the quaternarynitrogen atom an unsubstituted or a substituted heterocyclic ringselected from the group consisting of pyridinium, pyrimidinium,pyrazinium, 1-imidazolinium, oxazolium, thiazolium, pyrazolium, anddiaza[2,2,2]bicyclooctanium, wherein said substituted heterocyclic ringcarries at least one substituent selected from the group consisting of ahalogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, a free or esterified CO₂ R₄ groupas above defined, --C.tbd.N, --CONH₂, and phenyl; X⁻ is apharmaceutically acceptable anion, a salt, enantiomer, ordiastereoisomer thereof.
 2. A compound according to claim 1, wherein Ais a phosphonium group.
 3. A compound according to claim 1, wherein A isa quaternary ammonium group.
 4. A compound according to any one of thepreceding claims, wherein R is hydrogen, and R₂ is a phenyl groupunsubstituted or substituted by one or more C₁ -C₆ alkoxy, halo-C₁ -C₆alkyl, halo-C₁ -C₄ alkoxy, halogen, nitro, cyano, C₁ -C₆ alkoxycarbonyl,C₁ -C₆ alkylthio, C₁ -C₆ alkylsulphinyl groups.
 5. A compound accordingto claim 1, selected from the group consistingof:[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triethylphosphoniumchloride;[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]tributylphosphoniumchloride;[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;[(6-methyl-3,5-dicarboethoxy-4-(o-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;[(6-methyl-3,5-dicarboethoxy-4-(o-chlorophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;[(6-methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-1,4-dihyropyridin-2-yl)-methyl]triphenylphosphoniumchloride;[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumiodide;[(6-methyl-3-cyano-5-carboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]triphenylphosphoniumchloride;1-[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]pyridiniumchloride;1-[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]-3-carbamoylpyridinium chloride;1-[(6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-1,4-dihydropyridin-2-yl)-methyl]1,4-[2,2,2]-diazabicyclooctaniumchloride.
 6. A pharmaceutical composition for antihypertensive,antithrombotic, and antiischemic therapy, said composition comprising atherapeutically effective amount of a compound of claim 1, 2, 3, 5 or 6and a pharmaceutically acceptable carrier.